Transduction of a signal such as from the exterior to the interior of the cell is specific and finely tuned to insure a select cellular outcome. Propagation of a signal transduction event involves protein-protein interactions as in protein phosphorylation and substrate- enzyme reactions for example. Such events are highly enhanced in magnitude and specificity if the proteins involved are associated with, and concentrated in, the same membrane domains rather than distributed over a large number of disconnected domains (Thompson et al., 1995). We have shown that if a protein binds to a specific lipid, in a lipid mixture with an inherent tendency to demix, proteins and the lipid that it preferentially binds to will co-cluster (Hinderliter et al., 2001). This is a consequence of a thermodynamic coupling of the weak cooperative interactions between lipids, in this case phosphatidylserine (PS), and the specific interaction between positive charges on the membrane-binding face of the protein and the negatively charged PS. This clustering, or protein-induced lipid domain formation, is very sensitive to the concentration of PS and is also sensitive to the tendency of the lipid to demix within the membrane, which is modified by the lipid chemical structure of the individual lipids. Specific lipids such as PS, unless bound to proteins and essentially removed from possible reaction, would create unregulated hot spots for signaling by allowing ensembles of proteins that bind PS to cluster together. Lacking is a mechanism by which protein-induced membrane domains may be regulated. We hypothesize that annexins regulate membrane domains, necessitating a detailed understanding the molecular basis of annexin-membrane interactions. PUBLIC HEALTH RELEVANCE Annexins are an abundant family of membrane-associated proteins with diverse distribution in organisms, which bind phosphatidylserine and calcium ion, apparently without any enzymatic function. The malleability of the annexins is manifested in the allosteric transition model (Almeida et al., 2005) that describes their binding of ligand, of refolding, and potentially in protein-protein interactions. Annexins have a plasticity in how they interact with membranes. Within this context, annexins have the capacity to alter the lateral and transmembrane distribution of lipids with nuanced and discriminating ability. Proposed is how annexins regulate lipid distribution and generalities between annexins and disease-significant proteins are discussed.